Argatroban, a thrombin inhibitor, has been studied in the setting of both coronary perfusion as well as acute ischemic stroke. Since the majority of ischemic stroke patients may not benefit from rt-PA alone, the combination of thrombolytics with anticoagulants present a novel strategy for reperfusion. Primary specific aim: To assess the safety of combination rt-PA and Argatroban in acute ischemic stroke patients. Specifically, patients with large artery (proximal) occlusions will be included which can be identified on either CT-angiogram (CTA) or transcranial Doppler (TCD) ultrasound. Hypothesis: The combination of rt-PA and Argatroban will be safe in acute ischemic stroke. Rationale: The combination of thrombolytics and anticoagulation has proven efficacious in other disease treatments (e.g., cardiovascular disease). Pre-clinical work has shown improved microcirculation flow with Argatroban, reduced re-occlusion and increased rates of recanalization when delivered with thrombolytics. However, the combination ofthese two treatments have not been studied in acute ischemic stroke patients. Approach: Safety will be assessed by theincidence of sICH or PH-2. The primary measure of safety will be to not tolerate greater than a 10% rate of sICH or PH-2 within 48 hours. A total of 65 patients will receive standard-of-care intravenous IV-rtPA within 3 hours of symptom onset. Each patient will also receive Argatroban (100[unreadable]g/kg bolus followed by l[unreadable]g/kg/min infusion) for 48 hours started during the rt-PA infusion. The study will be a multi-center, prospective, open-label, single-arm, safety and activity clinical trial. Secondary aims: To explore the rates of early arterial recanalization and clinical recovery in ischemic stroke patients treated with combination intravenous rt-PA and Argatroban. Hypothesis: Combination rt-PA and Argatroban will result in greater rates of vessel recanalization. In addition, the combination will result in greater rates of clinical recovery. Rationale: Based on available ischemic stroke literature, IV rt-PA treatment alone produces complete recanalization at 2 hours at a rate of <15%. In addition, speed and completeness of recanalization is likely the PUBLIC HEALTH RELEVANCE: Data generated during this phase II study will evaluate the safety of a potentially effective combination treatment for acute stroke patients and provide preliminary evidence that the combination may produce more complete recanalization.